Burn injury is accompanied by marked changes in host defense. Despite advances in topical and systemic antimicrobial therapy and techniques of wound closure, sepsis remains the main cause of mortality in severely burned patients. Successful host defense and repair after thermal injury is, in part, dependent on the presence of adequate numbers of functionally competent highly motile myeloid cells such as granulocytes, monocytes, and macrophages. During two previous grant-funded periods, using our murine model of thermal injury + infection, we found: marked alterations in myeloid production, and function; were able to improve survival by administration of G-CSF, IL-1, or GM-CSF; G-CSF resulted in increased WBC and neutrophil counts, an increase in the number of femoral marrow granulocyte-macrophage progenitor cells (GM-CFC), peritoneal elicitation of granulocytes, and a restoration in defective neutrophil chemotaxis; cyclooxygenase inhibition caused an increase in GM-CFC numbers and WBC, that following burn + infection there is a marked alteration in GM-CFC DNA synthetic activity; in normals and burn animals, we can replicate this pattern with endotoxin and block this with indomethacin. Our hypothesis is that burn injury + infection alters myelopoieses via LPS mediated events resulting in enhanced macrophage PGE2 production. The specific aims for this grant are to: 1) Investigate the mechanisms controlling alterations in myeloid response following burn =/- infection; 2) Determine the mechanisms of action of exogenously administered hematopoietic growth factors. By use of our murine model of thermal injury, granulocyte- macrophage clonal culture, direct assessment of marrow proliferative activity with the tritiated thymidine suicide assay technique, assessment of granulocyte and macrophage function and analysis of macrophage secretor products, we will determine the networking which is occurring within this cell system, facilitating, as well as inhibiting, its response. Greater understanding of the alterations in the host defense subsequent to thermal injury will provide the basis upon which to formulate new treatment strategies.